The present disclosure relates to a method for preventing or reducing epithelial cell injury in a patient This epithelial cell injury results in mucositis, in particular stomatitis. In particular, the disclosure relates to a method for relieving oral discomfort and inflammation associated with anti-neoplastic therapy-induced mucositis.
Neutropenia results from anti-neoplastic treatment, in particular chemotherapy is a major factor contributing to infectious morbidity and mortality in cancer patients, Pizzo, et al., "Infections in the cancer patient" In: Cancer Principles and Practice of Oncology (2) and DeVita, et al. eds., 1985; 1963-1998. A reduction in the doses of chemotherapy which should be administered is often necessary due to the myelosuppressive toxicity of many anti-neoplastic agents. The inability to administer full doses of chemotherapy, in turn, is thought to impair (or adversely influence) the anti-tumor response of therapeutic protocols designed to treat cancer, DeVita, "Dose response is alive and well", J Clin Onc, 1986; 4:1157-1159. The ability to either accelerate recovery from or prevent chemotherapy-induced myelosuppression would clearly be of potential benefit. Dose limiting toxicity of anti-tumor agents involves not only deleterious effects on the cells of the bone marrow, but injures rapidly dividing epithelial cells of the oral mucosa and gastrointestinal tract. The compromised mucosa coupled with the myelosuppression effects of chemotherapy predispose patients to oral mucositis and subsequent secondary infection. Chemotherapy-induced stomatitis occurs as a result of either direct damage to cells of the oral mucosa or indirect injury associated with concomitant myelosuppression. Cancer chemotherapeutic agents which are known to produce direct stomatotoxicity include methotrexate, doxorubicin, vinblastine and the like. Patients having had prior radiation complicated by mucositis are subject to a "recall" reaction, whereby mucositis is exacerbated by further treatment with doxorubicin.
Combination chemotherapy for transitional cell carcinoma consisting of methotrexate, vinblastine, doxorubicin and cisplatin, commonly referred to collectively as "M-VAC" is a regimen capable of inducing complete and partial responses in 69% of patients; however, mucositis, leukopenia and the ensuing complication of fever and infection are a frequent consequence of this treatment. Other complications associated with chemotherapy or radiation therapy include alopecia, nausea and vomiting.
Mucositis is a generic term associated with inflammation of the mucosal lining with or without ulceration as a result of direct damage to the cells of the oral mucosa or indirect injury associated with concomitant myelosuppression. Anti-neoplastic therapy includes the use of cancer chemotherapeutic agents which produce direct stomatotoxicity including but not limited to methotrexate, doxorubicin, vinblastine, bleomycin, vincristine and the like. Illustrative of various types of mucositis include oral stomatitis, digestive tract ulcerations, gingivitis, and mucocutaneous ulcerations. In addition, other potential diseases related to mucositis include diseases associated with ulceration of intestinal tract (i.e. ulcerative colitis, Crohns disease etc.), autoimmune disease(s), (Behcets syndrome) and the like. Mucositis is commonly induced as a result of anti-neoplastic therapy which includes, for example, the use of cancer chemotherapeutic agents which interfere with both normal and malignant cell replication by having a mode of action affecting cell division or metabolism. Chemotherapy is frequently employed to treat malignant disorders and provides a systemic means for reducing or preventing malignant cell proliferation.
Conventional therapy utilized in the systemic treatment of diagnosed mucositis includes palliative therapy, such as administration of local anesthetics, i.e. viscous xylocaine; pain medication such as codeine with acetaminophen; treatment with agents that coat the lining of the mouth, such as substrate of milk of magnesia; sodium bicarbonate, 3% hydrogen peroxide, and the like. In addition, leucovorin, (D, L, N.sup.5 -formyl tetrahydrofolic acid) has been used to prevent mucositis associated with methotrexate. Antifungal agents have been shown only to prevent or reduce secondary fungal infection resulting from already established mucositis. In addition, acyclovir treatment has been used to treat mucocutaneous herpes infections occurring in the setting of chemotherapy induced mucositis. Typically, a patient suffering the effects associated with mucositis will have to reduce the amount of chemotherapy and may suffer additional complications including, for example, pain, hemorrhage, reduced nutritional intake, secondary infections and the like.
Recently, granulocyte colony stimulating factors (GCSF), a hematopoietic glycoprotein which controls the proliferation of granulocytes in vitro and in vivo have been purified, molecularly cloned and expressed as a recombinant protein, Souza, et al., "Recombinant human granulocyte colony stimulating factor; effects on normal and leukemic myeloid cells", Science 1986; 232:61-65. Administration of recombinant human granulocyte colony stimulating factor (rhG-CSF), a specific growth and differentiation factor for neutrophil granulocytes in vitro id , and in vivo in normal cynomolgous primates Welte, K., et al. "Recombinant human granulocyte colony stimulating factor effects on hematopoiesis in normal and cyclophosphamide treated primates", Jour. Ep. Med. 1987; 165 941-948, has also been shown to shorten the period of neutropenia in cynomolgous primates treated with either high dose cyclophosphamide id. busulfan, Welte, K , et al. "In vivo effects of recombinant human GCSF in therapy induced neutropenias in primates", ISEH. 1987; 16:72 or autologous transplantation, Gillio, A. P., et al. "Effects of recombinant human granulocyte colony stimulating factor on hematopoiesis reconstitution following autologous bone marrow transplantation in primates, Transplant Proc. 1987; In Press.